Synthesis of acronycine and related compounds

ABSTRACT

THE TOTAL SYNTHESIS OF ACRONYCINIC AND RELATED COMPOUNDS FROM READILY AVAILABLE STARTING MATERIALS IS DESCRIBED, AS ARE VARIOUS CLASSES OF INTRMEDIATES USEFUL IN THE SYNTHESIS.

United States Patent Ofice 3,732,204 SYNTHESIS OF ACRONYCINE AND RELATEDCOMPOUNDS James R. Beck, Indianapolis, Ind., assignor to Eli Lilly andCompany, Indianapolis, Ind.

No Drawing. Original application July 17, 1967, Ser. No. 653,667, nowPatent No. 3,624,087. Divided and this application July 6, 1971, Ser.No. 128,528

Int. Cl. C07d 37/12 US. Cl. 260-279 R 2 Claims ABSTRACT OF THEDISCLOSURE The total synthesis of acronycine and related compounds fromreadily available starting materials is described, as are variousclasses of intermediates useful in the synthesis.

CROSS-REFERENCE TO RELATED APPLICATION This application is a division ofco-pending application, Ser. No. 653,667, filed July 17, 1967 now Pat.No. 3,624,087.

BACKGROUND OF THE INVENTION Acronycine was first isolated fromAcronychia baueri by Lahey and co-workers [Nature 162, 223 (1948) andAust. J. Sci. Res. 2A, 423 (1949)]. The chemistry of acronycine wasdiscussed in further articles by Lahey and co-workers [Aust. J. Sci.Reg. 2A, 622, 630 1949)]. In 1966 it was determined by MacDonald andRobertson, Aust. J. Chem. 19, 275 (1966) and by Govindachari, Pai andSubramaniam, Tetrahedron 22, 3245 (1966) that acronycine had thefollowing structure:

OCH:

Patented May 8, 1973 myeloma.

SUMMARY This invention provides a method of synthesizing acronycinewhich comprises first cyclizingN-(fi-halopropionyl)-3,S-di-lower-alkoxyaniline to yield a5,7-di-loweralkoxy-3,4-dihydrocarbostyril, reaction of which with ano-halobenzoic acid under Ullmann conditions yields a 1- (2carboxyphenyl)-5,7-di-lower-alkoXy-3,4-dihydrocarbostyril. Treatment ofthe latter compound with a condensing agent such as polyphosphoric acidyields a ,mixture of a 3-(1,3-dialkoxy-9-oxo-4-acridanyl) propionic acidand the corresponding inner lactam. Esterification of this mixture withan alkanol yields a lower alkyl 3-(1,3-dialkoxy-9-oxo-4-acridanyl)propionate. This latter compound is nextselectively dealkylated to give a lower alkyl 3 (1 hydroxy3-lower-alkoXy-9-oxo-4-acridany1) propionate, alkylation of which withan alkyl lithium or lower-alkyl Grignard reagent yields a1-hydroxy-3-lower alkoxy 4(3-hydroxy-3,3-di-lower-alkylpropyl)-9-oxoacridane. Treatment of thislatter compound with acid yields a6-hydroxy-3,3-di-1ower-alkyl-2,3-dihydro-7(12H) lH-pyranol [2, 3 -ce]acridanone.

In the above reaction when there is no substituent present in theo-halobenzoic acid and where the alkylating agent is methyllthium ormethylmagnesium bromide, the resulting compound isN-desmethylnordihydroacronycine. N-methylation ofN-desmethylnordihydroacronycine followed by selective dehydrogenationusing dichlorodicyanoquinone (DDQ) yields noracronycine directly. 0-alkylation of noracronycine yields acronycine. The above synthesis canbe visualized in Reaction Scheme I which follows:

REACTION SCHEME I Oalk salt

fusion I II Olk

VII

l dealkylate O alk COOH III IV D 51" phosphoric R 0 1k lacid CHr-OHa-COOH H H o O alk-Ll f ethereal solvent N -Ol N o& 2 2 alk H H Hr-CHz-COOR'Hz-CHz-( VIII IX OH 1 acid alkylatlon alk XV =H (acronyclue) In theabove reaction scheme, X and X can be chlorine, bromine or iodine andalk is a lower-alkyl group having from 1 to carbon atoms, eitherstraight chained or branched chained, for example, methyl, ethyln-propyl, isopropyl, n-butyl, iso-butyl and the like; R can be hydrogen,halogen, nitro, trifiuoromethyl, alk, or Oalk; R is hydrogen, methyl,ethyl, benzyl; and R is methyl or ethyl.

As previously mentioned, the first step of our novel multi-stepsynthesis of acronycine involves the cyclization of anN-(B-halopropionyl)-3,5-di-lower-alkoxyaniline (I) to a5,1-dilower-alkoxy-3,4-dihydrocarbostyril (II). The cyclization iscarried out by the fusion of (I) with a mild, essentially anhydrous,Friedel-Crafts catalyst such as zinc chloride, zinc bromide, stannouschloride, antimony trichloride and the like, optionally in the presenceof an alkali metal halide. The fusion of (I) in the presence of one ofthe aforementioned heavy metal catalysts is carried out at a temperatureof about 50 C. to about 250 C., no solvent being required. In carryingout the cyclization of (I), We prefer to use zinc chloride in arelatively anhydrous state in combination with an alkali metal halide,such as sodium chloride, at a temperature of about 150 C. althoughhigher or lower temperatures are fully operative. Addition of two partsof sodium chloride to one part of the zinc salt has an advantageouselfect on the yield of (II).

In the second step, the 3,4-dihydrocarbostyril (II) is reacted with ano-halobenzoic acid (III) in the presence of cuprous iodide or othercuprous salt to yield the 1-(2- carboxyphenyl) 3,4-dihydrocarbostyril(IV). The reaction conditions are typically those used in the Ullmanreoptional alkylation action. The reaction is carried out in an inertsolvent, such as nitrobenzene, in the presence of a hydrogen halideacceptor, such as, potassium carbonate, sodium carbonate and the like ata temperature of about C. to about 250 C. We prefer to carry out thereaction of (II) with (III) where X is iodo in the presence of cuprousiodide in nitrobenzene at a temperature of about C. for 24 hours.

The 1-(2-carboxyphenyl)-3,4-dihydrocarbostyril (IV) produced in theabove reaction is then cyclized by treatmerit with polyphosphoric acidor other equivalent condensing agent at a temperature of about 50 C. toabout 150 C. to yield a mixture consisting of a 1,3-di-loweralkoxy 9oxo-4-acridanylpropionic acid (VI) and the corresponding inner lactam,2,3 dihydro-4,6-di-loweralkoxy 1H,7H-pyrido-[3,2,l-de]aeridine-1,7-dione(V) where alk and R are as defined above. This cyclization is preferablycarried out at a temperature of about 90 0, though higher or lowerreaction temperatures are fully operative.

The mixture comprising (V) and (VI) is next treated with 2 N methanolicor ethanolic hydrogen chloride at reflux temperature to yield theoptionally substituted methyl or ethyl 9-oxo-4-acridanylpropionate(VII), where R, R and alk are as defined above. During this reaction,the 2,3 dihydro 4,6 di-lower-alkoxy-1H,7H-pyrido- [3,2,1-de]acridine-1,7-dione (V) component of the above mixture is converted to(VII) by an alcoholysis reaction, and the acridanylpropionic acid (VI)component of the mixture is concurrently converted to (VII) byesterification. Thus, the separation of the mixture of (V) and (V1) isobviated by this one step methanolysisesterification reaction.

The 9-oxo-4-acridanylpropionate (VII) is then selectively dealkylated toyield a 1-hydroxy-3-rnethoxy-9-oxo- 4-acridanylpropionate (VIII), basedon the procedure of F. M. Dean et al., Tetrahedron Letters, 4153-4159(1966), which procedure utilizes boron trichloride in an inert solventas the dealkylating agent. Alternatively, this selective dealkylation ofthe l-alkoxy group of (VII) to obtain (VIII) has been carried out with aGrignard reagent in an ether-pyridine solvent system at a temperature ofabout 60 C. In this alternate procedure, the preferred Grignard reagent,selected from among the lower alkylmagnesium bromides or iodidesforexample methylmagnesium iodide in etheris first mixed with pyridine.Next a pyridine solution of (VII) is added. The reaction mixture is thenheated for about four hours at a temperature of about 60 C. to yield(VIII). We prefer, however, to carry out the selective demethylation of(VII) by the aforementioned procedure based upon that of F. M. Dean etal., loc. cit. According to this procedure (VII) is dissolved inmethylene chloride and the solution treated with excess gaseous borontrichloride at a temperature of about C. The reaction is carried tocompletion by allowing the mixture to remain at ambient temperature for30 minutes. Excellent yields of the 1-hydroxy-3-alkoxy-9-oxo-4-acridanylpropionate (VIII) are thus obtained.

The monohydroxy compound (VIII) is next reacted with a loweralkyllithium where lower alkyl is the same as defined above, in anethereal solvent such as diethyl ether, tetrahydrofuran or diethyleneglycol dimethyl ether, to yield a tertiary carbinol (IX). In thisreaction, the alkyllithium converts the propionate ester group to atertiary alcohol. The reaction is carried out at a temperature in therange 7 0 C. to 0 C. in an inert atmosphere of a gas such as nitrogen.We prefer to carry out the preparation of (IX) in the solventtetrahydrofuran at a temperature of about -20 C. with a reaction time ofabout 30 minutes to obtain maximal yields of the tertiary carbinol.

Upon treatment of the tertiary carbinol (IX) with 48 percent hydrobromicacid in glacial acetic acid at or near reflux temperature cyclizationoccurs inovlving the 3-alkoxy substituent and the tertiary hydroxylgroup of (IX) to yield the 3,3-di-lower-alkyl-2,3-dihydro-7(12H)-lH-pyrano[2,3-c]acridinone (X). Preferably, however, the abovecyclization is carried out by fusing (IX) with pyridine hydrochloride ata temperature of about 200 C. The reaction is usually complete afterabout four hours. (X) is obtained in a purified state by columnchromatography over silica gel or similar material in a benzeneethylacetate solvent combination. Alternatively, we find it advantageous incarrying out our synthesis to convert (X) in the crude state to the moreeasily isolatable (XI) by the N-alkylation of (X) with a methyl halide,an ethyl halide or a benzyl halide in refluxing acetone in the pressenceof potassium carbonate. The above cyclization reaction whereby an alkoxygroup undergoes cleavage, followed by intramolecular cyclization with atertiary carbinol, is unique and indeed is a key step in the totalsynthesis of acronycine and related compounds. The product of the abovealkylation (X) where R' is H is classified as aN-desmethylnordihydroacronycine but when R is other than hydrogen, thecompound is classified as a dihydronoracronycine. Treatment of eitherthe normal or the N-desmethyl derivative with a quinone having a highstandard oxidation potential (E), preferably in the neighborhood of 1.0volt in an inert solvent, yields a 6-hydroxy-3,3-dilower alkyl 1,2dihydro pyrano [2,3 ce]acn'- dinone (XIII). We prefer to carry out thisdehydrogenation with 2,S-dichloro-5,6-dicyanobenzoquinone (DDQ) inrefluxing toluene over a 1-3 hour period. This unique method for theintroduction of the carbon to carbon double bond in the dihydropyranylring of (X) or (XI) affords surprisingly high yields.

In carrying out the series of reactions depicted in Reaction Scheme I,where R is H, R and alk are methyl,

dihydronoracronycine was obtained (XI). Oxidation ofdihydronoracronycine with DDQ as described above afforded noracronycineidentical in physical and chemical properties to the naturalnoracronycine reported by D. Brown, L. J. Drumond, F. H. Lahey and W. C.Thomas, Australian J. Sci. Research A2, 423 (1949). Methylation ofnoracronycine by the method of R. D. Brown et al., loc. cit. yieldedacronycine.

The above synthetic procedure when carried out with compounds in whichalk and R are methyl andR is hydrogen yields acronycine which, as hasbeen previously stated, has been found to be extremely useful in thetreatment of experimental tumors in mice and is a potential addition tothe armamentarium of anti-neoplastic drugs. The process of thisinvention is also useful for preparing compounds related to acronycinein which alk, R and R are other than as specified as acronycine. Thesecompounds, as well as compounds related to noracroncyine [(XIII Where Ris other than hydrogen and alk is methyl] have an effect on the centralnervous system which is generally a stimulating action, although certainof the compounds have sedative effects. Compounds corresponding toFormulas II, IV, V, VI, VII, VIII, IX and X all represent novelstructures and are all useful as intermediates for the preparation ofacronycine and related compounds as represented by XV.

Further aspects and equivalents of the present invention will becomeobvious to one skilled in the art. The following examples further definethe present invention but are not intended in any way to limit the scopeof the invention.

EXAMPLE 1 5 ,7 -dimethoxy-3 ,4-dihydrocarbostyril One hundred thirtygrams of 3,5-dimethoxy-N-(B-bromopropionyl) aniline and 75 g. of zincchloride (previously dried for 2 hours at C.) were fused at 150 C. for30 minutes. The reaction mixture was allowed to cool to room temperatureand the 5,7-dimethoxy-3,4-dihydrocarbostyril formed in the abovereaction was extracted therefrom with 400 ml. of ethyl acetate. Theextract was washed successively with 400 ml. of 3 N hydrochloric acid,with a staturated solution of sodium bicarbonate and with a saturatedsolution of sodium chloride. The extract was separated and dried, andthe solvent removed therefrom to yield 17 g. of5,7-dimethoxy-3,4-dihydrocarbostyril melting at about 192l94 C. afterrecrystallization from methyl alcohol.

Analysis-Cale. (percent): C, 63.75; H, 6.32; N, 6.76. Found (percent):C, 63.83; H, 6.64; N, 6.76.

EXAMPLE 2 5,7-dimethoxy-3,4-dihydrocarbostyril (zinc chloridesodiumchloride method) One hundred forty grams of3,5-dimethoxy-N-(fi-bromopropionyl) aniline were added rapidly to amixture, previously dried at C. for 2.5 hours, consisting of 70 g. ofzinc chloride and 140 g. of sodium chloride at a temperature of about155 C. The reaction mixture was maintained at a temperature of about 155C. for 20 minutes, cooled to room temperature, and5,7-dimethoxy-3,4-dihydrocarbostyril formed in the above reaction wasextracted therefrom with 500 ml. of ethyl acetate. The extract waswashed successively with 400 m1. of 3 N hydrochloric acid, water asaturated solution of sodium bicarbonate, and a saturated solution ofsodium chloride. The extract was separated and dried and the solventevaporated therefrom in vacuo. The resulting residue yielded 16.9 g. of5,7- dimethoxy-3,4-dihydrocarbostyril melting at about 192- 194 C. afterrecrystallization from ethanol. The mother liquor was evaporated invacuo to yield 100 g. of an oil consisting of partially demethylatedproduct. The oil was treated with a mixture of 300 ml. of methyl iodideand 240 g. of potassium carbonate in one-liter of acetone at refluxtemperature for 72 hours. The reaction mixture was cooled, filtered, andthe solvent evaporated in vacuo. An additional 11.7 g. of5,7-dimethoxy-3,4-dihydrocarbostyril melting at about 195196 C. afterrecrystallization from methanol were obtained from the residue.

Analysis.Calcd. (percent): C, 63.75; H, 6.32; N, 6.76. Found (percent):C, 63.83; H, 6.64; N, 6.76.

EXAMPLE 3 l-(Z-carboxyphenyl)-5,7-dimethoxy-3,4- dihydrocarbostyrilEight grams of 5,7-dimethoxy-3,4-dihydrocarbostyril and 19.8 g. of2-iodobenzoic acid were reacted together in the presence of 0.5 g. ofcupious iodide, 0.2 g. of cupric acetate monohydrate, 16 g .of potassiumcarbonate and 175 ml. of nitrobenzene. The reaction mixture wasmaintained at a temperature of about 150 C. for 24 hours with continualstirring, and was then steam distilled to remove the nitrobenzene. Theaqueous mixture was filtered and acidified.l-(2-carboxyphenyl)-5,7-dimethoxy- 3,4-dihydrocarbostyril, formed in theabove reaction, was extracted therefrom with 400 ml. of ethyl acetate.The organic extract was washed with a saturated solution of sodiumchloride which was discarded. The carbostyril was extracted from theorganic layer with a saturated aqueous solution of sodium bicarbonate.The sodium bicarbonate extract was acidified and the productre-extracted with ethyl acetate. The ethyl acetate extract was dried,and the ethyl acetate removed therefrom by evaporation in vacuo. Threegrams of l-(2-carboxyphenyl)-5,7-dimethoxy-3,4- dihydrocarbostyril wereobtained from the resulting residue melting at about 223225 C. afterrecrystallization from methyl alcohol.

Analysis.-Calcd. (percent): C, 66.05; H, 5.24; N, 4.28. Found (percent)C, 65.83; H, 5.37; N, 4.22.

EXAMPLE 4 Methyl-3 1 3-dimethoxy-9-oxo-4-acridanyl -propionate Fourgrams of 1-(2-carboxyphenyl)-5,7-dimethoxy-3,4- dihydrocarbostyrilprepared as in Example 3, and 160 ml. of polyphosphoric acid were mixedtogether and the mixture heated at about 100 C. for 1.5 hours. Thereaction mixture was poured over 400 g. of crushed ice, yielding a solidprecipitate which was filtered and dried by azeotropic distillation. Thedried precipitate was dissolved in 100 ml. of 1 N methanolic hydrogenchloride and the solution refluxed for 2.5 hours. The solvent wasremoved therefrom by evaporation in vacuo to yield 3.7 g. of a residueconsisting essentially of methyl 3-(1,3-dimethoxy-9-oxo-4-acridanyl)-propionate. Suspension of the residue in 400 ml. of asaturated sodium bicarbonate solution, followed by separation andrecrystallization of the thus obtained product, gave purified methyl3-(1,3-dimethoxy- 9-oxo-4-acridanyl)-propionate melting at about 244-245 C.

Analysis.Calc. (percent): C, 66.85; H, 5.61; N, 4.10. Found (percent):C, 66.81; H, 5.64; N, 4.07.

EXAMPLE 5 Methyl 3-( 1-hydroxy-3-methoxy-9-oxo-4-acridanyl)- propionateFour grams of methyl 3-(1,3-dimethoxy-9-oxo-4-acridanyl)-propionate,prepared as in Example 4, were dissolved in 300 ml. of methylenechloride and the solution treated with an excess of gaseous borontrichloride at a temperature of 5 C. The reaction mixture was thenallowed to remain at room temperature for 30 minutes after which time300 ml. of water were added. The methylene chloride layer containingmethyl 3-( l-hydroxy-3-methoxy- 9-oxo-4-acridanyl)-propionate formed inthe above reaction was separated and washed successively with 300 ml.water, 300 ml. of a saturated solution of sodium chloride. The washedmethylene chloride layer was dried and the solvent evaporated therefromyielding as a residue 3 g. of

8 methyl 3 (1-hydroxy-3-methoxy-9-oxo-4-acridanyl)-propionate melting atabout 194l95 C. after recrystallization from a chloroform-ethyl alcoholsolvent mixture.

Analysis.Calc. (percent): C, 66.05; H, 5.24; N, 4.28. Found (percent):C, 65.91; H, 5.67; N, 3.94.

EXAMPLE 6 Methyl 3-(1-hydroxy-3-methoxy-9-oxo-4-acridanyl)- propionate(Grignard method) To an ethereal solution of methylmagnesium iodideprepared in the usual manner from 200 mg. of magnesium and 0.3 ml. ofmethyl iodide, 10 ml. of dry pyridine were carefully added followed bymg. of methyl 3- (l,3-dimethoxy-9-oxo-4-acridanyl) propionate dissolvedin 15 ml. of pyridine. The reaction mixture was heated at a temperatureof about 50 C. to about 60 C. for 20 hours and then poured over anice-water mixture. The methyl 3-(l-hydroxy-3-methoxy-9-oxo-4-acridanyl)propionate formed in the above reaction was extracted into chloroform,and the extract separated and washed with a saturated solution ofammonium chloride. The organic layer was then dried and the solventevaporated therefrom in vacuo. 144.2 milligrams of methyl 3-( l-hydroxy-3-methoxy-9-oxo-4-acridanyl)-propionate Were obtained, melting at about194195 C. after recrystallization from aqueous methanol.

EXAMPLE 7 1-hydroxy-4-(3-hydroxy-3-methylbutyl) -3-methoxy- 9-acridanoneSix-hundred fifty milligrams of methyl 3-(l-hydroxy-3-methoxy-9-oxo-4-acridanyl)-propionate, prepared as in Example 5, weredissolved in 50 ml. of tetrahydrofuran and reacted with 10 ml. of a 1.7molar solution of methyllithium in diethyl ether at a temperature of 19C. The above reaction was carried out under nitrogen with continualstirring. After about 30 minutes, the reaction mixture was decomposedwith 100 ml. of a 3 N hydrochloric acid and the1-hydroxy-4-(3-hydroxy-3-methylbutyl)-3-methoxy-9-acridanone formed inthe above reaction was extracted therefrom with 200 ml. of ethylacetate. The extract was washed successively with 200 ml. of a saturatedsolution of sodium chloride, 200 ml. of a saturated solution of sodiumcarbonate and again with a saturated solution of sodium chloride. Theextract was dried and the solvent evaporated therefrom. 683 milligramsof 1-hydroxy-44(3-hydroxy-3-methyl-butyl) 3 methoxy-9- oxoacridanonewere obtained, melting at about 213 2l4 C. after recrystallization fromethyl acetate.

Analysis.-Calc. (percent): C, 69.70; H, 6.47; N, 4.28. Found (percent):C, 69.41; H, 6.44; N, 4.27.

EXAMPLE 8 6-hydroxy-3,3-dimethyl-2,3-dihydro-7 1 2H) -lH- pyrano [2,3-c]-acridinone Nine-hundred eighty-five milligrams of 1-hydroxy-4-(3-hydroxy-3-methylbutyl)-3-methoxy 9 acridanone, prepared as in Example 7,were heated with 25 g. of pyridine hydrochloride at a temperature of toC. for 3 hours. The product of the reaction,6-hydroxy-3,3-dimethyl-2,3-dihydro-7(l2H) 1H pyrano[2,3-c]-acridinone,crystallized from the reaction mixture on the addition of 200 ml. ofwater and was collected by filtration. The compound was purified bychromatography, using a 5:1 benzene-ethyl acetate eluant over a columnpacked with 60 g. of silica gel. Thirty-five fractions of 22 ml. eachwere collected at a flow rate of 88 ml. per hour. Fractions 15 to 29were combined and evaporated in vacuo, and the solid residuerecrystallized from a chloroform-ethanol solvent mixture to yield 84 mg.of purified 6-hydroxy-3,3-dimethyl 2,3 dihydro-7(l2H) 1Hpyrano[2,3-c]-acridinone melting at about 273 274 C.

Analysis.-Calc. '(percent): C, 73.20; H, 5.80; N, 4.74. Found (percent):C, 73.38; H, 5.65; N, 4.56.

9 EXAMPLE 9 Nordihydroacronycine Forty-seven milligrams of6-hydroxy-3,3-dimethyl-2,3- dihydro 7(12H)-1H-pyrano[2,3-c]-acridinone,prepared as in Example 8, were dissolved in 50 ml. of acetone andreacted with ml. of methyl iodide at reflux temperature for 5 hours inthe presence of 4 g. of potassium carbonate. The reaction mixture wasfiltered and then diluted with 100 ml. of water. The acetone was removedby evaporation and nordihydroacronycine, formed in the above re action,was extracted from the aqueous layer with 100 m1. of ethyl acetate. Theextract was washed with 100 ml. of a saturated solution of sodiumchloride, dried, and the ethyl acetate removed therefrom by evaporationin vacuo. 19.7 milligrams of nordihydroacronycine were obtained, meltingat about 205 2l2 C. after recrystallization from chloroform-ethanol.

Analysis.Calc. (percent): C, 73.77; H, 6.19; N, 4.53. Found (percent):C, 73.61; H, 6.11; N, 4.53.

EXAMPLE 1O Noracronycine 309.4 mililgrams of nordihydroacronycine,prepared as in Example 9, and 249.7 mg. of2,3-dichloro-5,5-dicyanoquinone were reacted in 125 ml. of toluene atreflux temperature for 1.5 hours. The reaction mixture was cooled toroom temperature, and diluted with 125 ml. of ethyl acetate. The dilutedreaction mixture, after being washed successively with 250 ml. of a 5%solution of sodium hydroxide and with 250 ml. of a saturated solution ofsodium chloride, was dried and the solvent evaporated in vacuo to yield300 mg. of a solid residue containing noracronycine. The noracronycinewas purified by chromatography using a 30:1 benzene-ethyl acetateeluant, over a column packed with 200 g. of silica gel. One hundred andforty fractions were collected of ml. each. Fractions 84 to 103 werecombined and evaporated in vacuo to yield 144 mg. of noracronycinemelting at about 200 to 200.5 C. after recrystallization from ethylacetate.

EXAMPLE 11 6-hydroxy-3,3-diethyl-10-nitro-2,3-dihydro-7(12H)- lH-pyrano[2,3-c] acridinone Following the procedure of Example 1,3,5-di-n-propoxy-n-fl-chloropropionylaniline can be fused in thepresence of stannous chloride and sodium chloride to yield5,7-di-n-propoxy-3,4-dihydrocarbostyril. Reaction of this compound with4-nitro-2-iodobenzoic acid under Ullmann conditions yields l-(Z-carboxy5 nitrophenyl)-5,7-di-npropoxy-3,4-dihydrocarbostyril. Treatment of thislatter compound with polyphosphoric acid followed by esterification ofthe resulting product with ethanolic hydrogen chloride gives ethyl3-(1,3-di-n-propoxy-6-nitro-9-oxo-4- acridanyl)-propionate, selectivede-etherification of which yields the corresponding l-hydroxyderivative. Reaction of this latter compound with ethyllithium givesl-hydroxy- 4-(3-hydroxy 3 ethylpentyl)-3-n-propoxy-6-nitro-9-acridanonetreatment of which with pyridine hydrogen chlo- 10 ride yields 6-hydroxy3,3 diethyl-l0-nitro-2,3-dihydr0- 7 12H)-1H-pyrano [2,3-c] acridinone.

Following the same procedure, but using an appropriately substitutedo-halobenzoic acid and the proper alkylating agent, ether alkyl lithiumor Grignard reagent, the following compounds can be prepared:

6-hydroxy-3 ,3-di-n-propyll0-chloro-2,3-dihydro- 7 12H lH-pyrano [2,3-c]-acridinone 6-hydroxy-3 ,3-di-isobutyl-8-methyl-2,3-dihydro- 7 12H -1H-pyrano [2, 3-0] -acridinone 6-hydroxy-3,3-di-n-butyl-8-trifluoromethyl-2,3-dihydro- 7 12H) -1H-pyrano [2,3-c]-acridinone 6-hydroxy-3,3-di-ethyl-9-ethoXy-2,3-dihydro-7( 12H)1H-pyrano[2,3-c] -acridinone I claim: 1. The compound of the formula III1 CH3 mula CHa

which comprises heating a compound of the formula with a member selectedfrom the group consisting of pyridine hydrochloride and 48 percenthydrobromic acid.

References Cited FOREIGN PATENTS 1/ 1970 France 260-279 OTHER REFERENCESBeck et al.: Jour. Am. Chem. Soc., vol. 89, p. 3934.

DONALD G. DAUS, Primary Examiner

